1H-benzimidazole-5-carboxamides as anti-inflammatory agents

Abstract

There are provided compounds of formula (I), wherein R 1 , R 6 , R 8 , Q 2 , Q 3 , Q 3a , Q 4 , L and A have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a member of the MAPEG family is desired and/or required, and particularly in the treatment of inflammation and/or cancer.

The invention claimed is: 
     
       1. A compounds of formula Ia, Ib or Ic: 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents C 1-3  alkyl optionally substituted by one or more fluoro atoms, C 3-6  cycloalkyl, fluoro, chloro, bromo; 
         R 2  represents hydrogen, C 1-3  alkyl optionally substituted by one or more fluoro atoms, C 3-6  cycloalkyl, fluoro, chloro, bromo; 
         R 3 , R 3a  and R 4  independently represent hydrogen, fluoro, chloro, bromo, C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         R 6  represents hydrogen or C 1-6  alkyl optionally substituted by one or more substituents selected from fluoro, —N(R y1 )R y2 , —N(R y3 )—C(O)—R y4 , —N(R y5 )—S(O) 2 —R y6 , —C(O)OR y7 , —C(O)N(R y8 )R y9 , —OR y10 , —S(O) 2 R y11  and a 4- to 6-membered heterocycloalkyl group containing two or one heteroatom(s) selected from oxygen and nitrogen; 
         R 8  independently represents hydrogen, fluoro, chloro, bromo, —OR y10  or C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         A represents phenyl, 2-pyridyl, C 3-10 cycloalkyl, C 1-12  linear or branched alkyl, all of which are optionally substituted by one or more substituents selected from R 9 ; 
         R 9  represents on each occasion when used herein: halo, —CN, —N(R y1 )R y2 , —N(R y3 )—C(O)—R y4 , —N(R y5 )—S(O) 2 —R y6 , —C(O)OR y7 , —C(O)N(R y8 )R y9 , —OR y10 , —S(O) m —R y11 , —S(O) 2 O—R y12 , —S(O) 2 N(R y13 )R y14  and/or —C(O)R y15 , C 1-6 alkyl optionally substituted by one or more substituents selected from halo, —CN, —N(R y1 )R y2 , —N(R y3 )—C(O)—R y4 , —N(R y5 )—S(O) 2 —R y6 , —C(O)OR y7 , —C(O)N(R y8 )R y9 , —OR y10 , —S(O) m —R y11 , —S(O) 2 O—R y12 , —S(O) 2 N(R y13 )R y14  and/or —C(O)R y15 ;
 aryl or heteroaryl, which latter two groups are optionally substituted by one or more groups selected from C 1-7  alkyl optionally substituted by one or more substituents selected from fluoro and —OR x2 ; halo; —CN and/or —O—C 1-7  alkyl optionally substituted by one or more fluoro atoms; or 
 any two R 9  substituents, 
 when attached to the adjacent atoms of the A group and, 
 in the case where the R 9  substituents are attached to a non-aromatic A group, 
 when attached to the same atoms, 
 may be linked together to form, together with the essential atoms of the A group to which the relevant R 9  substituents are necessarily attached, a further 3- to 8-membered ring, optionally containing a further one or two heteroatoms, and which further ring optionally contains one or two unsaturations and which is optionally substituted by one or more C 1-3  alkyl and/or ═O substituents; 
 
         each R y4 , R y6 , R y11  and R y15 :
 independently represent C 1-4  alkyl; 
 
         and 
         each R x2 , R y1 , R y2 , R y3 , R y5 , R y7 , R y8 , R y9 , R y10 , R y12 , R y13 ,and R y14  :
 independently represent hydrogen or C 1-4  alkyl optionally substituted by one or more substituents selected from halo atoms and —OC 1-2 -alkyl; or 
 any two of these groups, when attached to the same nitrogen atom, that is R y1  and R y2 , R y8  and R y9 , or R y13  and R y14 , may, together with that nitrogen atom to which they are necessarily attached, be linked together to form a 3- to 8-membered ring, which ring is optionally containing one or two further nitrogen or oxygen heteroatoms and optionally containing one or two double bonds in the ring and optionally substituted by one or more C 1-3  alkyl and/or ═O substituents, 
 
         with the proviso that: if R 6  is hydrogen; and R 8  independently are hydrogen, C 1-3  alkyl optionally substituted with one or more fluoro atoms or —OR y10  represents C 1-7  alkyl or cycloalkyl which latter two groups are optionally substituted with one or more fluoro atoms; 
         then A is not phenyl or 2-pyridyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. A compound of formula Id, Ie or If: 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents chloro, bromo, fluoro, C 1-3  alkyl which latter alkyl group is optionally substituted by one or more fluoro-atoms; 
         R 2  represents hydrogen, chloro, bromo, fluoro, C 1-3 -alkyl which latter alkyl group is optionally substituted by one or more fluoro atoms; 
         R 3 , R 3a  and R 4  independently represent hydrogen, chloro, bromo, fluoro, C 1-3 -alkyl which latter alkyl group is optionally substituted by one or more fluoro atoms; 
         R 6  represents hydrogen; C 1-4  alkyl optionally substituted by one or more fluoro atoms; 
         R 8  represent hydrogen, fluoro, chloro, —O—C 1-4  alkyl optionally substituted by one or more fluoro atoms; 
         A represents phenyl, 2-pyridyl, C 3-10  cycloalkyl, C 1-12  alkyl, all of which are optionally substituted by one or more substituents selected from R 9 ; 
         R 9  represents, on each occasion when used herein:
 halo, —OR y10 ; C 1-7  alkyl, cycloalkyl, which latter two groups are optionally substituted by one or more fluoro atoms; or 
 aryl, heteroaryl which latter two groups are optionally substituted by one or more substituents selected from halo; C 1-7  alkyl, cycloalkyl which latter two groups are optionally substituted by one or more fluoro atoms; —O—C 1-3  alkyl which latter group is optionally substituted by one or more fluoro atoms; 
 
         and
 R y10  represents hydrogen or C 1-4  alkyl, optionally substituted by one or more substituents selected from halo atoms and —OC 1-2  alkyl; 
 
         with the proviso that: if R 6  is hydrogen and R 8  is hydrogen or —O—C 1-4  alkyl aptionally substituted with one or more fluoro atoms, 
         then A is not phenyl or 2-pyridyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. A compounds according to  claim 1 , which is selected from the following compounds or a pharmaceutically acceptable salt thereof:
 Compound Compound Name 
 Number 
 409 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-6-carboxamide; 
 410 N-(4-Bromophenyl)-2-(3,5-dichloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide; 
 435 2-(3,5-dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1-methyl-1H-benzimidazole-5-carboxamide; 
 446 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-5-carboxamide; 
 467 2-(3,5-Dichloropyridin-4-ylamino)-1-methyl-N-(2-trifluoromethyl-benzyl)-1H-benzimidazole-5-carboxamide; 
 493 2-(3,5-Dichloropyridin-4-ylamino)-N-(2-trifluoromethyl-benzyl)-1H-benzimidazole-5-carboxamide; 
 520 N-(4-Bromophenyl)-2-(3-chloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide; 
 531 2-(2-Chloro-4-methylpyridin-3-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-5-carboxamide; 
 532 N-(4-Bromophenyl)-1-methyl-2-(3-trifluoromethyl-pyridin-4-ylamino)-1H-benzimidazole-5-carboxamide; 
 547 N-Cyclohexyl-2-(3,5-dichloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide; 
 553 2-(3,5-Dichloropyridin-4-ylamino)-1-methyl-N-((3-trifluoromethyl-pyridin-2-yl)methyl)-1H-benzimidazole-5-carboxamide; 
 565 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)methyl)-1H-benzimidazole-5-carboxamide; 
 567 N-(4-Bromophenyl)-1-methyl-2-(3-methylpyridin-4-ylamino)-1H-benzimidazole-5-carboxamide 
 660 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromophenyl)-6-propoxy-1-methyl-1H-benzimidazole-5-carboxamide; 
 666 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromophenyl)-6-(2-methoxy-ethoxy)-1-methyl-1H-benzimidazole-5-carboxamide; 
 667 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 668 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-ethoxy-1-methyl-1H-benzimidazole-5-carboxamide; 
 669 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 670 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-ethoxy-1-methyl-1H-benzimidazole-5-carboxamide; 
 671 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-(2-methoxy-ethoxy)-1-methyl-1H-benzimidazole-5-carboxamide; 
 672 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-dimethylamino-1-methyl-1H-benzimidazole-5-carboxamide; 
 673 2-(3,5-Dichloro-pyridin-4-yl-amino)-6-fluoro-N-(4,4-dimethyl-cyclohex-1-yl)-1H-benzimidazole-5-carboxamide; 
 674 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohex-1-yl)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxamide; 
 675 2-(3,5-Dichloro-pyridin-4-yl-amino)-6-(2,2,2-trifluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzimidazole-5-carboxamide; 
 677 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-(2-fluoroethoxy)-1H-benzimidazole-5-carboxamide; 
 683 2-(3,5-Dichloro-pyridin-4-ylamino)-6-methoxy-N-(2,2,3,3,4,4,5,5,5-nonafluoro-penthyl)-1H-benzimidazole-5-carboxamide; 
 686 2-(3,5-Dichloro-pyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-(2-methoxy-ethoxy)-1H-benzimidazole-5-carboxamide; 
 688 2-(3,5-Dichloro-pyridin-4-ylamino)-N-((3-cyclobutyl-pyridin-2-yl)-methyl)-6-methoxy-1H-benzimidazole-5-carboxamide; 
 689 2-(3,5-Dichloropyridin-4-ylamino)-N-((2-trifluoromethyl-phen-1-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 690 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 691 2-(3,5-Dichloropyridin-4-ylamino)-N-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 693 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-chloro-pyridin-2-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide; 
 700 2-(3,5-Dichloro-pyridin-2-yl-amino)-N-(2,2,3,3,4,4,5,5,5-nonafluoro-pentyl)-6-(difluoromethoxy)-1H-benzimidazole-5-carboxamide; 
 701 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-difluoromethoxy-1H-benzimidazole-5-carboxamide; 
 704 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromo-phenyl)-6-ethoxy-1-(2,2,2-trifluoroethoxy)-1H-benzimidazole-6-carboxamide; or 
 711 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-difluoromethyl-pyridin-2-yl)-methyl)-6-(2,2,2-trifluoro-ethoxy)-1H-benzimidazole-5-carboxamide. 
 
     
     
       4. A pharmaceutical formulation comprising a compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
       5. A method for the treatment of a disease or condition selected from: asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, a neurodegenerative disorder, an autoimmune disease, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, any other disease with an inflammatory component, osteoporosis, osteoarthritis, Paget's disease, a periodontal disease or a cancer, in a patient comprising administering to said patient a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       6. A pharmaceutical formulation comprising a compound according to  claim 2 , or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
       7. A method for the treatment of a disease or condition selected from: asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, a neurodegenerative disorder, an autoimmune disease, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, any other disease with an inflammatory component, osteoporosis, osteoarthritis, Paget's disease, a periodontal disease or a cancer, in a patient comprising administering to said patient a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof.